A5054846899- Cell Adhesion Molecules Research
- Cerebrovascular and genetic disorders
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Connective tissue disorders research
- Barrier Structure and Function Studies
- Cellular Mechanics and Interactions
- Platelet Disorders and Treatments
- Hemispheric Asymmetry in Neuroscience
- Renal and related cancers
- Skin and Cellular Biology Research
- Wnt/β-catenin signaling in development and cancer
- Genetic factors in colorectal cancer
- Dermatoglyphics and Human Traits
- Caveolin-1 and cellular processes
- Moyamoya disease diagnosis and treatment
- Tissue Engineering and Regenerative Medicine
- Protease and Inhibitor Mechanisms
- Dermatological and Skeletal Disorders
- Nuclear Receptors and Signaling
- Bone and Dental Protein Studies
- Medical and Biological Ozone Research
- Histiocytic Disorders and Treatments
- Genetic Associations and Epidemiology
- Cardiac Fibrosis and Remodeling
- Clusterin in disease pathology
University of Glasgow
2016-2025
Barcelona Institute for Science and Technology
2024
Institute for Bioengineering of Catalonia
2024
Massachusetts General Hospital
2021
Broad Institute
2021
Inserm
2009-2014
Academy of Athens
2014
Université Toulouse III - Paul Sabatier
2014
Universitätsklinikum des Saarlandes
2014
University of Plymouth
2014
COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies humans. However, causative for a number of hereditary multicystic kidney diseases, myopathies with cramps, heritable intracranial aneurysms remain unknown.
Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. We recently described hereditary angiopathy with nephropathy, aneurysm, muscle cramps (HANAC) syndrome in 3 families closely localized mutations. The aim of this study was to describe the cerebrovascular phenotype HANAC.
Accumulation of extracellular matrix in organs and tissues is a feature both aging disease. In the kidney, glomerulosclerosis tubulointerstitial fibrosis accompany decline function, which current therapies cannot address, leading to organ failure. Although histologic ultrastructural patterns excess form basis human disease classifications, comprehensive molecular resolution abnormal lacking.
Abstract Vascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to limited understanding of underlying mechanisms. We aimed identify the molecular insults mutations, focusing on collagen folding, establish if targeting protein folding represents potential therapeutic approach. Analysis two novel glycine G189S and G906R, in primary patient fibroblast cultures revealed secretion misfolded III intracellular...
Members of the type IV collagen family are essential components all basement membranes (BMs) and define structural stability as well tissue-specific functions. The major isoform, α1.α1.α2(IV), contributes to formation many BMs its deficiency causes embryonic lethality in mouse. We have identified an allelic series three ENU induced dominant mouse mutants with missense mutations gene Col4a1 encoding α1(IV) subunit chain. Two severe alleles ( Bru Svc ) affecting conserved glycine residues...
The ability of tendons to glide smoothly during muscle contraction is impaired after injury by fibrous adhesions that form between the damaged tendon surface and surrounding tissues. To understand how we incubated excised in fibrin gels (to mimic homeostatic environment at site) assessed cell migration. We noticed cells exiting from only cut ends. Furthermore, treatment with trypsin resulted extravagation shaft tendons. Electron microscopy immunolocalisation studies showed are covered a...
Objective Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening known cSVD genes identifies the causative mutation in <15% familial cases. We sought to identify novel causes cSVD. Methods used linkage analysis and exome sequencing causal French family. The identified candidate gene was then screened 202 unrelated probands, including 1 proband from first reported pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) Sanger confirm...
Haemorrhagic stroke accounts for ∼20% of cases and porencephaly is a clinical consequence perinatal cerebral haemorrhaging. Here, we report the identification novel dominant G702D mutation in collagen domain COL4A2 (collagen IV alpha chain 2) family displaying with reduced penetrance. obligatory protein partner COL4A1 but contrast to most mutations, does not lead eye or kidney disease. Analysis dermal biopsies from patient his unaffected father, who also carries mutation, revealed that both...
Collagen type IV is the major structural component of basement membrane and COL4A1 mutations cause adult small vessel disease, familial porencephaly hereditary angiopathy with nephropathy aneurysm cramps (HANAC) syndrome. Here, we show that animals a Col4a1 missense mutation ( Col4a1+/Raw ) display focal detachment endothelium from media age-dependent defects in vascular function including reduced response to nor-epinephrine. Age-dependent hypersensitivity acetylcholine abolished by...
Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There critical need provide mechanistic insight improve translation between pre-clinical research the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, cardiovascular biology, highlight current advances these fields, explore synergies scope for development. These proceedings summary...
Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke vascular cognitive impairment. Risk factors include old age, hypertension variants the genes
ABSTRACT Collagen IV is a major component of basement membranes, and mutations in COL4A1, which encodes collagen alpha chain 1, cause multisystemic disease encompassing cerebrovascular, eye kidney defects. However, COL4A1 renal remains poorly characterized its pathomolecular mechanisms are unknown. We show that Col4a1 mice hypotension disease, including proteinuria defects Bowman's capsule the glomerular membrane, indicating role for filtration. Impaired sodium reabsorption loop Henle distal...
Abstract The blood–brain barrier (BBB) tightly regulates substance transport between the bloodstream and brain. Models for study of physiological processes affecting BBB, as well predicting permeability therapeutic substances neurological neurovascular pathologies, are highly desirable. Existing models, such Transwell utilizing‐models, do not mimic extracellular environment BBB with their stiff, semipermeable, non‐biodegradable membranes. To help overcome this, we engineered electrospun...
IntroductionX-linked Alport syndrome (OMIM 301050) is caused by COL4A5 missense variants in 40% of families. This study examined the effects chemical chaperone treatment (sodium 4-phenylbutyrate) on fibroblast cell lines derived from men with mutations.MethodsDermal cultures were established 2 affected and 3 normals. Proliferation rates examined, collagen IV α5 chain localized immunostaining, levels intra- extracellular chains quantitated an in-house enzyme-linked immunosorbent assay. mRNA...
The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of ECM contributes to broad range neurological disorders. However, despite this importance, our understanding composition remains very limited mainly due difficulties in its isolation. To address this, we developed an approach extract cerebrovascular from mouse human post-mortem normal We then used mass spectrometry with off-line high-pH reversed-phase fractionation...
White matter abnormalities are a central feature of cerebral small vessel disease (cSVD) and underpin cognitive impairment dementia but their mechanistic link remains poorly understood. To provide insight we studied mice (Col4a1+/Svc) with mutation in the gene Col4a1 as an established model cSVD due to collagen IV mutations. Since is key component basement membrane, specialised extracellular matrix structure (ECM), hypothesised that would disrupt ECM cause white abnormalities....
Mutations in the collagen genes COL4A1 and COL4A2 cause Mendelian eye, kidney cerebrovascular disease including intracerebral haemorrhage (ICH), common IV variants are a risk factor for sporadic ICH. mutations endoplasmic reticulum (ER) stress basement membrane (BM) defects, recent data suggest an association of ER with ICH due to mutation. However, potential as therapeutic target multi-systemic pathologies remains unclear. We performed preventative oral treatment Col4a1 mutant mice chemical...